Use of PDE III inhibitors for the treatment of asymptomatic (occult) heart failure

ABSTRACT

The invention relates to the use of a phosphodiesterase type III (PDE III) inhibitor or Ca 2+ -sensitizing agent or a pharmaceutically acceptable derivative thereof for the preparation of a medication for the prolongation of time until onset of clinical symptoms in patients having an asymptomatic (occult) heart failure or for the reduction of heart size in patients having symptomatic or asymptomatic (occult) heart failure.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 11/087,465, which was filed on Mar. 23, 2005 and which claimspriority to EP Application No. 04007179, which was filed on Mar. 25,2004 and was published as EP 1579862 A1, and is also acontinuation-in-part of U.S. patent application Ser. No. 11/559,467,which was filed on Nov. 14, 2006 and which claims priority to EPApplication No. 05110689, which was filed on Nov. 14, 2005 and waspublished as EP 1951227 A2, all of which applications are incorporatedby reference herein in their entirety.

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates to the use of a phosphodiesterase type III (PDEIII) inhibitor or a “Ca²⁺-sensitizing agent” or a pharmaceuticallyacceptable derivative thereof for the preparation of a medication forthe reduction of the heart size of a patient suffering from heartfailure, and a medication for the reverse remodelling of the heart of apatient with asymptomatic (occult) heart failure and their delayed onsetof clinical symptoms.

2. Background Information

Heart failure is divided in different stages (ISACHC-Stages-ClassI-III). The pathology of the heart begins with ISACHC Class I in whichcardiac murmur or cardiac chamber enlargement, but no clinical symptomsare present (Class I or occult stage). Heart insufficiency scoring isused herein, and the following is a description of the scoring so used.

Degree of heart insufficiency was evaluated using a 5-class scoreadapted from the International Small Animal Cardiac Health Council(ISACHC) System of Heart Failure Classification:

Class I: The Asymptomatic Patient (Heart Disease Associated with NoClinical Signs)

-   -   Heart disease is detectable (e.g. cardiac murmur, arrhythmia, or        cardiac chamber enlargement that is detected by radiography or        echocardiography); however the patient is not overtly affected        and does not demonstrate clinical signs of heart failure. The        need for treatment at this stage is arguable but not justifiable        with currently available data.    -   The stage is subdivided as follows:    -   A.: Signs of heart disease are present but no signs of        compensation (volume or pressure overload ventricular        hypertrophy) are evident (Class IA).    -   B.: Signs of heart disease are present and signs of compensation        (volume or pressure overload ventricular hypertrophy) are        detected radiographically or echocardiographically (Class IB).

Class II: Mild-to-Moderate Heart Failure

-   -   Clinical signs of heart failure are evident at rest or with mild        exercise, and adversely affect the quality of life. Typical        signs of heart failure include exercise intolerance, cough,        tachypnoea, mild respiratory distress (dyspnoea), and mild to        moderate ascites. Hypoperfusion at rest is generally not present        (Class II). Home treatment is often indicated at this stage.

Class III: Advanced Heart Failure

-   -   A.: Clinical signs of advanced congestive heart failure are        immediately obvious. These clinical signs could include        respiratory distress (dyspnoea), marked ascites, profound        exercise intolerance, or hypoperfusion at rest. In the most        severe cases, the patient is moribund and suffers from        cardiogenic shock. Death or severe debilitation is likely        without therapy.    -   B.: Patients with advanced heart failure are divided into two        Subcategories:        -   1. Home care is possible (Class IIIA).        -   2. Hospitalisation is mandatory (cardiogenic shock,            life-threatening oedema, or a large pleural effusion is            present) (Class IIIB).

It is known that the progress of heart failure is associated with anincrease of the size of the heart. In dilated cardiomyopathy (DCM), theratio of left ventricular wall thickness to chamber diameter isdecreased and the circumferences of the annuluses of the mitral andtricuspid valves are increased in proportion to the magnitude of chamberdilation. DCM may either be caused primarily, e.g. by geneticabnormalities, or secondarily, e.g. due to valvular insufficiency, bothresulting in cardiac volume overload. However, it involves usuallycardiac remodeling that may be defined as genome expression, molecular,cellular, and interstitial changes manifested clinically as changes insize, shape, and function of the heart. Cardiac remodelling is generallyan adverse sign and linked to heart failure progression. Reverse cardiacremodelling is a goal of the treatment of heart failure therapy.

Heart failure therapy has traditionally focused largely on symptomaticrelief rather than on addressing underlying disease problems. Many dogswith symptomatic DCM have a very guarded prognosis (Monnet et al.,1995), with Dobermanns in particular generally experiencing only shortsurvival times (Calvert et al., 1982; Calvert et al., 1997). There havebeen few studies examining the influence of treatment on survival indogs with symptomatic DCM, although a subanalysis of the dogs with DCMin the LIVE study showed an improvement in time to treatment failure inthose dogs receiving enalapril compared with placebo (142.8 versus 56.5days, respectively) (Ettinger et al., 1998). On the whole, oral positiveinotropic agents have lost favour in the treatment of chronic heartfailure in human patients in recent years, after a number of trialsrevealed adverse effects on survival despite short-term hemodynamicbenefits (Packer et al., 1991; Cowley and Skene, 1994). Recently it hasbeen suggested that calcium sensitising agents may result in positiveinotropic effects without producing some of the adverse effects(including calcium overload) associated with more traditional positiveinotropes such as dobutamine, amrinone and milrinone.

In ISACHC Class I stage heart failure, in which cardiac murmur orcardiac chamber enlargement, but no clinical symptoms are present,therapy would have two objectives:

-   -   reduce the pathologic changes of the dimensions of the heart (to        the normal parameters—“reverse remodelling”); and    -   prolong the time until onset of clinical symptoms.

However, there is currently no drug available which has proven to beefficacious in the reduction of the pathologic changes of the dimensionsof the heart to the normal parameters (“reverse remodelling”) atasymptomatic stage (ISACHC Class I). A study has been published with theuse of ACE-Inhibitors in the asymptomatic stage, but no therapeuticeffect was shown (SVEP Trial), neither a reverse remodelling nor aprolongation of the time until onset of clinical symptoms.

When the pathology progresses and clinical symptoms are also present(Class II or III), several drugs showed a benefit in quality of life andsome also in survival time. These drugs include phosphodiesterase typeIII (PDE III) inhibitors or “Ca²⁺-sensitizing agents”, for examplecilostazol, pimobendan, milrinone, levosimendan, amrinone, enoximone andpiroximone TZC-5665, etc. Rather than increasing calcium entry intocardiac myocytes, calcium sensitisers achieve their positive inotropiceffect by sensitising the contractile proteins to existing cytosoliccalcium, by altering the binding of calcium with troponin-C. Producing apositive inotropic effect by calcium sensitising thereby avoids some ofthe adverse effects of cytosolic calcium overload. Increased cytosoliccalcium levels have been associated with an increased tendency forarrhythmias and sudden death. Clinical trials of long-term use of oralpimobendan in human patients with heart failure have demonstrated animprovement in exercise tolerance and quality of life withoutsignificantly adverse effects on survival (Kubo et al., 1992; Katz etal., 1992).

The problem underlying the present invention was to provide amedication, which increases the time without clinical symptoms andremodels the size of the heart to reduce the risk of death in patientswith asymptomatic heart disease (ISACHC Class I).

BRIEF DESCRIPTION OF THE INVENTION

It has surprisingly been found that phosphodiesterase type III (PDE III)inhibitors and/or Ca²⁺-sensitizing agents, preferably pimobendan, orpharmaceutically acceptable derivatives thereof can be used for thepreparation of a medication able to prolong the time until onset ofclinical symptoms and for the reduction of the heart size in cases ofasymptomatic (occult) heart failure, e.g. asymptomatic DCM.

Moreover, the invention relates to a method of reduction of the heartsize in cases of asymptomatic (occult) heart failure, e.g. asymptomaticDCM, which method comprises administering to a patient having anasymptomatic heart failure, e.g. asymptomatic DCM, an effective amountof an PDE III inhibitor, preferably pimobendan, or a pharmaceuticallyacceptable derivative thereof.

Furthermore, the invention relates to an article of manufacturecomprising packaging material contained within which is a compositioneffective to prolong the time until onset of symptoms and to reduce theheart size of a patient having an asymptomatic (occult) heart failure,e.g. asymptomatic DCM, and the packaging material comprises a labelwhich indicates that the composition can be used to prolong the timeuntil onset of symptoms and to reduce the heart size of a patient havingan asymptomatic (occult) heart failure, e.g. asymptomatic DCM, whereinsaid composition comprises at least one PDE III inhibitor or aCa²⁺-sensitizing agent, preferably pimobendan, or a pharmaceuticallyacceptable derivative thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the lateral thoracic radiograph of an English cockerspaniel with dilated cardiomyopathy, showing alveolar pulmonary oedemaand cardiac enlargement.

FIGS. 2 a and 2 b show the thoracic radiograph of the same dog in FIG.1, following four months treatment with furosemide, enalapril, digoxin,and pimobendan.

FIG. 3 shows the Heart Insufficiency Score (ISACHC) in dogs treated withpimobendan (each left black column) or benazepril (each right greycolumn) on days 0, 7 and 56.

FIG. 4 shows the Overall Clinical Effect in dogs treated with pimobendan(left black column) or benazepril (right grey column) on day 56.

FIG. 5 shows the survival function (56-day period) in dogs treated withpimobendan (upper-◯-curve) or benazepril (lower-□-curve).

FIG. 6 shows the survival function in dogs treated with pimobendan(430-day period/upper-◯-curve) or benazepril (228-dayperiod/lower-□-curve).

FIG. 7 shows reduction in mean heart size for pimobendan treated dogs(−0.15 v) versus benazepril treated dogs (+0.22 v).

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to the use of a phosphodiesterase type III (PDEIII) inhibitor, preferably a PDE III inhibitor, a Ca²⁺-sensitizingagent, or a PDE III inhibitor which exhibits additionally calciumsensitising effects (Ca²⁺-sensitizing agent), or a pharmaceuticallyacceptable derivative thereof for the preparation of a medication forthe prolongation of the time until onset of clinical symptoms of theheart disease and the reduction of the heart size of a patient having anasymptomatic (occult) heart failure, e.g. asymptomatic DCM.

The term “PDE III inhibitor” as used hereinabove and hereinbelow relatesto phosphodiesterase (PDE) III inhibitors, which prevent breakdown ofcAMP to 5′AMP and thus maintain the effect of cAMP on protein kinase andother secondary messenger activation.

The effects of PDE III inhibitors are as a rule positive inotropy andvasodilatation, which reduces the afterload and makes patients withheart failure feel better.

The term Ca²⁺-sensitizing agent relates to a compound which increasesthe Ca²⁺ sensitivity of cardiac contractile proteins, i.e. increase thedeveloped contractile force at a given concentration of Ca²⁺.

Preferred PDE III inhibitors or Ca²⁺-sensitizing agents are cilostazol,pimobendan, milrinone, levosimendan, amrinone, enoximone and piroximoneTZC-5665 or pharmaceutically acceptable salts, derivatives, metabolitesor pro-drugs thereof. Most preferred are pimobendan and levosimendan, orpharmaceutically acceptable salts, derivatives, metabolites or pro-drugsthereof. Even more preferred is pimobendan and levosimendan. Even morepreferred is pimobendan, pharmaceutically acceptable salts, derivatives,metabolites or pro-drugs thereof.

Pimobendan, known to the public as4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazol-5-yl]-5-methyl-3(2H)-pyridazone,is for example disclosed in EP 008 391 B1. Levosimendan is apyridazone-dinitrile derivative known to the public as(R)-[[4-(1,4,5,6-Tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile,which has been described earlier for example in GB 2228004, U.S. Pat.No. 5,151,420 and U.S. Pat. No. 5,569,657.

The term “patient” as used hereinabove and hereinbelow relates to ananimal or a person having symptomatic, e.g., DVM, or asymptomatic(occult) heart failure, e.g. asymptomatic DCM. The term “patient”embraces mammals such as primates including humans.

In addition to primates, a variety of other mammals can be treatedaccording to the method of the present invention. For instance, mammals,including but not limited to, cows, sheep, goats, horses, dogs, cats,guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodentor murine species can be treated. However, the method can also bepracticed in other species, such as avian species.

Preferred are human patients, dogs, cats and horses. Human patients arefemale or male persons, having symptomatic or asymptomatic (occult)heart failure, e.g. asymptomatic DCM. As a rule such persons arechildren, young adults, adults or elderly people with an age of between6 and 80, preferably between 30 and 65 years.

The term “heart failure” as used hereinabove and hereinbelow relates toany contractile disorder or disease of the heart. Clinicalmanifestations are as a rule the results of changes to the heart'scellular and molecular components and to mediators that drivehomeostatic control. Heart failure is as a rule accompanied by anincrease of the heart size and deterioration of cardiac functions.Predominantly, the patients suffer from heart failure that is a chroniccongestive heart failure, a heart failure due to myocardial infarctionor myocardial ischemia due to cardiac arrest.

The term “asymptomatic heart disease” as used hereinabove andhereinbelow relates to any contractile disorder or disease of the heartwithout clinical symptoms of heart failure. In particular, it relates toheart failure of ISACHC-Stages-Class I. More particular, it relates to aDCM of ISACHC—Stages—Class I.

The term “reduction of the heart size” as used hereinabove andhereinbelow relates to a reduction of the size of the heart of apatient, which is diagnosed using echocardiography, or according to theradiograph methods suggested by James W. Buchanan et al. (Buchanan1995). The reduction is expressed in the relative change of thevertebral heart size. Preferably for a symptomatic patient, the relativemean vertebral heart sum (VHS) of said patient is reduced by 0.05 to0.25 within 10 to 100 days, in particular by about 0.15 within about 60days, of treatment with the PDE III inhibitor and/or Ca²⁺-sensitizingagent.

The term “prolongation until onset of clinical symptoms” as usedhereinabove and hereinbelow relates to the time from diagnosing thechanges of the heart until the beginning of clinical symptoms of heartfailure. In particular, it relates to the prolongation from heartfailure of ISACHC Class I to Class II and further to Class III. It moreparticular relates to the prolongation from heart failure of DCM ofISACHC Class I to Class II and further to Class III.

The term “effective amount” as used herein means an amount sufficient toachieve a prolongation of the time until onset of clinical symptoms andreduction of the heart size when said PDE III inhibitor orCa²⁺-sensitizing agent is administered in a single dosage form.

According to a further embodiment of the present invention, the PDE IIIinhibitor and/or Ca²⁺-sensitizing agent is administered in combinationwith a second active therapeutic agent. Such a second active therapeuticagent is preferably selected from the group consisting of calciumchannel blockers, ACE inhibitors, diuretics, platelet inhibitors, betablockers and angiotensin II antagonists, aldosterone antagonists,digitalis glycosides, anti-arrhythmic agents or diuretics, and inparticular:

-   -   wherein the calcium channel blocker inhibitor is selected from        the group consisting of diltiazem, verapamil and felodipine or a        pharmaceutically acceptable derivative thereof; and/or    -   wherein the ACE inhibitor is selected from the group consisting        of omapatrilat, MDL100240, alacepril, benazepril, captopril,        cilazapril, delapril, enalapril, enalaprilat, fosinopril,        fosinoprilat, imidapril, lisinopril, perindopril, quinapril,        ramipril, ramiprilat, saralasin acetate, temocapril,        trandolapril, trandolaprilat, ceranapril, moexipril, quinaprilat        and spirapril or a pharmaceutically acceptable derivative        thereof; and/or    -   wherein the beta blocker is selected from the group consisting        of bisoprolol, carvediol, metoprolol, propranolol and timolol or        a pharmaceutically acceptable derivative thereof; and/or    -   wherein the angiotensin II antagonist is selected from the group        consisting of saralasin acetate, candesartan, cilexetil,        valsartan, candesartan, losartan potassium, eprosartan,        irbesartan, tasosartan, pomisartan and telmisartan or a        pharmaceutically acceptable derivative thereof; and/or    -   wherein the aldosterone antagonist is selected from the group        consisting of spironolactone, eplerenone, canrenone, potassium        canrenone or a pharmaceutically acceptable derivative thereof,        and/or    -   wherein the anti-arrhythmic agents are selected from the group        consisting of amiodarone, betrylium, disopyramide, dofetilide,        flecamide, ibutilide, mexiletine, tocainide, procainamide,        propafenone, quinidine, sotalol or a pharmaceutically acceptable        derivative thereof, and/or    -   wherein the diuretic is selected from the group consisting of        furosemide, torasemide, bumetanide, etacrynic acid, azosemide,        muzolimine, piretanide, tripamide, bendroflumethazide,        chlorothiazide, hydrochlorothiazide, hydroflumethiazide,        methychlothiazide, polythiazide, trichlormethiazide,        chlorthialidone, indapamide, metolazone, quinethazone, etozolin,        triamteren, amiloride, or a pharmaceutically acceptable        derivative thereof; and/or    -   wherein the digitalis glycosides is selected from the group        consisting of digoxin, digitoxin, g-strophantin,        β-methyldigoxin, β-acetyldigoxin or a pharmaceutically        acceptable derivative thereof.

Most preferably, the PDE III inhibitor or Ca²⁺-sensitizing agent,preferably pimobendan or levosimendan, even more preferred pimobendan isadministered together with one or more medicaments selected from thegroup consisting of one or more ACE-inhibitors, one or more diureticsand one or more digitalis glycosides.

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the disorder.

By way of general guidance, the daily oral dosage of each activeingredient, preferably of pimobendan or levosimendan, when used for theindicated effects, will range between about 10 μg/kg to 10 mg/kg,preferably from 0.05 mg/kg to 5 mg/kg, in particular from 0.1 mg/kg to 2mg/kg. Most preferably from about 0.1 mg/kg to 1.5 mg/kg of pimobendanare administered per day.

The PDE III inhibitors and/or Ca²⁺-sensitizing agents may beadministered in a single daily dose, or the total daily dosage may beadministered in divided doses of two, three, or four times daily.

The PDE III inhibitors and/or Ca²⁺-sensitizing agents can beadministered in intranasal form via topical use of suitable intranasalvehicles, or via transdermal routes, using transdermal skin patches.When administered in the form of a transdermal delivery system, thedosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

The PDE III inhibitors and/or Ca²⁺-sensitizing agents are typicallyadministered in admixture with suitable pharmaceutical diluents,excipients, or carriers (collectively referred to herein aspharmaceutical carriers) suitably selected with respect to the intendedform of administration, that is, oral tablets, capsules, elixirs, syrupsand the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and colouring agents can also be incorporated into the mixture.Suitable binders include starch, gelatine, natural sugars such asglucose or beta-lactose, corn sweeteners, natural and synthetic gumssuch as acacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The PDE III inhibitors and/or Ca²⁺-sensitizing agents can also beadministered in the form of liposome delivery systems, such as smallunilamellar vesicles, large unilamellar vesicles, and multilamellarvesicles. Liposomes can be formed from a variety of phospholipids, suchas cholesterol, stearylamine, or phosphatidylcholines.

The PDE III inhibitors and/or Ca²⁺-sensitizing agents may also becoupled with soluble polymers as targetable drug carriers. Such polymerscan include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues.

Furthermore, the PDE III inhibitors and/or Ca²⁺-sensitizing agents maybe coupled to a class of biodegradable polymers useful in achievingcontrolled release of a drug, for example, polylactic acid, polyglycolicacid, copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacylates, and cross linked or amphipathicblock copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit.

In these pharmaceutical compositions the active ingredient willordinarily be present in an amount of about 0.5-95% by weight based onthe total weight of the composition.

Gelatine capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain colouring andflavouring to increase patient acceptance.

In general, water, suitable oil, saline, aqueous dextrose (glucose), andrelated sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where two or more of the foregoing second therapeutic agents areadministered with the PDE III inhibitor and/or Ca²⁺-sensitizing agent,generally the amount of each component in a typical daily dosage andtypical dosage form may be reduced relative to the usual dosage of theagent when administered alone, in view of the additive or synergisticeffect of the therapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when two therapeutic agents are combined in a single dosageunit they are formulated such that although the active ingredients arecombined in a single dosage unit, the physical contact between theactive ingredients is minimized (that is, reduced). For example, oneactive ingredient may be enteric coated. By enteric coating one of theactive ingredients, it is possible not only to minimize the contactbetween the combined active ingredients, but also, it is possible tocontrol the release of one of these components in the gastrointestinaltract such that one of these components is not released in the stomachbut rather is released in the intestines. One of the active ingredientsmay also be coated with a material which effects a sustained-releasethroughout the gastrointestinal tract and also serves to minimizephysical contact between the combined active ingredients.

Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

Procedures by way of example for preparing the compositions according tothe invention will be described in more detail hereinafter. The Exampleswhich follow serve solely as a detailed illustration without restrictingthe subject matter of the invention. The study was done in symptomaticdogs.

Example 1

A double-blind study has been carried out in order to evaluate thelong-term efficacy and tolerance to pimobendan and its effect onlong-term survival in cocker spaniels and Dobermanns with DCM.

Materials and Methods: Cocker spaniels (n=10) and Dobermanns (n=10)presenting to the Cardiopulmonary Service of the R(D)SVS with DCM wererecruited for the study with owners' consent. After stabilisation onconventional therapy with digoxin, enalapril, and furosemide, dogsreceived in addition either pimobendan (Vetmedin®) or placebo using adouble-blind study design.

Results: The mean survival time for cocker spaniels on pimobendan was612 days (range 61-1428) compared to 589 (range 51-1127) for the placebogroup. The difference was not statistically significant(Wilcoxon-Mann-Whitney-U test, p>0.05).

The mean survival time for Dobermanns on pimobendan was 280 days (range42-369) compared to 72 days (range 13-196) for the placebo group. Thedifference was statistically significantly different (Student's t-test,p<0.05). The drug was well tolerated and no treatment-related adverseeffects were noted in either breed.

Conclusion: Pimobendan significantly improved the survival time of theDobermanns with DCM compared with placebo, but had no statisticallysignificant effect on survival of the cocker spaniels. The improvedsurvival time for the Dobermanns is an important development in themanagement of a disease that generally results in rapid death followingdiagnosis.

In both breeds the addition of pimobendan to a standard treatmentregimen was associated with a significant improvement of the NYHA-classstatus of the patient. The benefit of pimobendan therapy was thereforeadditive to the beneficial effect of furosemide, enalapril and digoxin,and was even seen in the cocker spaniels which had what would beconsidered a favourable clinical course with conventional therapy,compared with many dogs with DCM (Monnet et al., 1995).

A striking difference in survival times was found in the Dobermanpinschers treated with pimobendan. Although this breed is known to havea poor prognosis after development of congestive signs, a significantprolongation of survival time was found for pimobendan-treated animals.

Example 2

A double-blind randomised positive controlled multi-centre field trialhas been carried out in order to evaluate the clinical efficacy ofpimobendan treatment at a daily dose of 0.4-0.6 mg/kg in comparison toan angiotensin-converting-enzyme (ACE) inhibitor treatment withbenazepril hydrochloride at a daily dose of approximately 0.25-0.5 mg/kgbody weight. Both treatments could be combined with furosemide (up to 8mg/kg per day) or anti-arrhythmic drugs as appropriate. The study wasconducted at 11 centres in Europe by experienced veterinarycardiologists under the rules of Good Clinical Practice (GCP). Mandatoryminimum duration of treatment was 56 days for each patient. Dogs wereexamined on Day 0 prior to first treatment and on Day 7 and 56 afterinitiation of therapy. In order to obtain long-term survival data, theinvestigator had the option to continue therapy after Day 56. In theoptional study period treatment code for the animal was decoded, as itwas not allowed to add pimobendan to the benazepril group, in order tomaintain an appropriate pimobendan control group. All other licensedconcomitant therapies were allowed. For survival analysis, animals thatdropped out or changed treatment due to therapy failure were also ratedas dead. However, these cases were statistically evaluated as censoreddata.

Primary parameter for conclusion on efficacy was the clinical severityof heart failure symptoms, classified according to the recommendationsof the International Small Animal Cardiac Health Council (ISACHC).Secondary parameters were exercise tolerance, demeanour, findings of therespiratory and circulatory system, overall efficacy rating, as well as,echocardiography data.

Overall 76 dogs, 41 dogs in the pimobendan group and 35 dogs in thebenazepril group, were included. All dogs showed clinically overtsymptoms of heart failure due to valve insufficiency. Mean duration ofsymptoms prior to inclusion was 4.05 months in the pimobendan and 2.77months in the benazepril group. There were no clinically relevantdifferences between the groups prior to initiation of therapy in any ofthe parameters investigated.

The primary parameter, ISACHC heart failure classification, was improvedin 84% of the pimobendan treated cases but only in 56% of the benazeprilcases after the 56 day treatment period. At this time point ISACHCclassification Ib (Score=2), i.e. no clinical symptoms, was reported for76% of the pimobendan but only 48% of the benazepril cases. Differencesbetween the groups regarding the primary parameter, were statisticallysignificant in favour of pimobendan on Day 7 (p=0.0280) and Day 56(p=0.0201). Consequently, overall efficacy was rated as very good orgood in 85% of the pimobendan cases but only in 41% of the benazeprilcases (p<0.0001). Results in other secondary parameters were inaccordance with the clinical results of the heart failureclassification.

In the 56-days study period, 2 dogs in the pimobendan group and 7 in thebenazepril group died or were euthanised due to cardiac reasons.Survival analysis according to Kaplan-Meier revealed significantdifferences in favour of pimobendan (p=0.0386). Analysis of long-termsurvival data confirmed the results of the 56-day period. Mediansurvival time for pimobendan treated dogs was 430 days versus 228 daysfor dogs that received no pimobendan. Again, survival analysis accordingto Kaplan-Meier revealed significant differences in favour of pimobendan(p=0.0020).

The radiographs have been made in a left to right lateral view. For thedetermination of cardiac size a vertebral scale system was used.

In the lateral radiographs, the long axis of the heart (L) was measuredwith a calliper extending from the ventral aspect of the left main stembronchus (tracheal bifurcation hilus, carina) to the most distantcontour of the left ventricular apex. The calliper was repositionedalong the vertebral column beginning at the cranial edge of the 4^(th)thoracic vertebra. The length of the heart was recorded as the number ofvertebrae caudal of that point and estimated to the nearest 0.1 of avertebra. The maximum perpendicular short axis (S) was measured in thesame manner beginning at the 4^(th) thoracic vertebra.

The length in vertebrae (v) of the long and short axes were then addedto obtain a vertebral heart sum (VHS) which provided a single numberrepresenting heart size proportionate to the size of the dog. The normalrange of VHS in healthy dogs is 8.5 v to 10.5 v (mean of 9.7 v).

The mean vertebral heart sum measured on radiographs on days 0 and 56showed improvement for dogs in the pimobendan group. With regards to thechanges from baseline, the difference in the mean value indicated areduction in mean heart size for pimobendan treated dogs. The meandifference between the groups regarding overall clinical efficacy wasstatistically significant in favour of pimobendan treatment (p<0.0001).See Table 1. The mean scores in the control benazepril group showeddeterioration with regard to changes from baseline (FIG. 7). Thisdemonstrates that a reduction of heart size cannot routinely be achievedwith standard therapy in dogs with heart failure due to valveinsufficiency. The striking difference between standard therapy(ACE-inhibitor+/−diuretics) deterioration of mean heart size by 0.22 vand pimobendan treatment with an improvement of mean size of −0.15 v wasunexpected and thus inventive.

TABLE 1 Vertebral scale system - heart sum. Visit Group N Min. Max.Median Mean SD 1 1 41 9 14.5 11.60 11.83 1.31 3 1 37 9.0 14.1 11.6011.71 1.18 3-1 1 37 −1.9 0.8 0.00 −0.15 0.57

Example 3

A study is done with pimobendan (Vetmedin®) in dogs suffering of occultdilated cardiomyopathy.

Inclusion criteria were dogs which are diagnosed to have a congestiveheart failure of class I according to the ISACHC—score due to dilatedcardiomyopathy (DCM). Dogs having a having an asymptomatic (occult)heart failure, e.g. asymptomatic DCM must have reduced contractility ofthe heart or other signs of reduced cardiac efficacy such as volumeoverload or ventricle dilatation as confirmed by echocardiography. Thedogs stay under mono-therapy until signs of congestive heart failure aredeveloping, deteriorate to heart insufficiency score (ISACHC) class IIor III a or b. After confirmation of the congestion by X-ray—radiographythe dogs receive furosemid treatment or if the clinical orechocardiographic results makes the addition of another heart failuretreatment necessary (primary endpoint). The dogs will be investigated atday 0 prior to first treatment and then approximately 3 month postinitiation of the therapy. In order to get long time survival data theinvestigators' makes then control visits will be repeated every 3-6months. An Echo is performed prior to initiation of therapy (Day 0) andat the following visits to support the clinical diagnosis and toevaluate the effect of the drugs on the contractility of the heart. Theechocardiography is performed according to the cardiologic case reportform for Irish Wolfhounds The primary parameter investigated will be theheart insufficiency score (ISACHC). Other parameters will be exercisetolerance, findings of the respiratory and circulatory system as well asechocardiography data.

Results:

After 4 years the interim analysis showed that significantly less dogstreated with pimobendan went into the state of clinical symptoms (ClassII)

A Left Ventricular Reverse Remodeling (LVRR,=Normalising of the size andfunction of the left ventricle) has been shown in dogs treated withPimobendan (ca 80%).

Since other studies in dogs with asymptomatic heart failure with otherdrugs could not show a prolongation until onset of clinical symptomsthese results were unexpected and thus inventive. Furthermore no otherstudy has been shown in dogs with asymptomatic heart disease a reverseremodeling in heart failure and thus the results were unexpected andthus inventive.

REFERENCES

-   Buchanan J W, et al. (1995) Vertebral Scale System to measure canine    heart size in radiographs. JAVMA, Vol. 206, No. 2, 194-199-   Calvert, C. A., Chapman, W. C., and Toal, R. C. (1982) Congestive    cardiomyopathy in Doberman Pinscher dogs. Journal of the American    Veterinary Medical Association 181: 598-602.-   Calvert, C. A., Pickus, C. W., Jacobs, G. J., and Brown, J. (1997)    Signalment, survival, and prognostic factors in Doberman Pinschers    with end-stage cardiomyopathy. Journal of Veterinary Internal    Medicine 11: 323-326.-   Cohn J N, et al. (2000) Cardiac Remodeling—Concepts and Clinical    implications: A Consensus Paper From an International Forum on    Cardiac Remodeling. J. of the American College of Cardiology, Vol.    35, No. 3, 569-582-   Cowley, A. J. and Skene, A. M. (1994) Treatment of severe heart    failure: quantity or quality of life? A trial of enoximone. British    Heart Journal 72: 226-230.-   Ettinger, S. J., Benitz, A. M., Ericsson, G. F., Cifelli, S.,    Jernigan, A. D., Longhofer, S L, Trimboli, W., and    Hanson, P. D. (1998) Effects of enalapril maleate on survival of    dogs with naturally acquired heart failure. The Long-Term    Investigation of Veterinary Enalapril (LIVE) Study Group. Journal of    the American Veterinary Medical Association 213: 1573-1577.-   Katz, S. D., Kubo, S. H., Jessup, M., Brozena, S., Troha, J. M.,    Wahl, J., Cohn, J. N., Sonnenblick, E. H., and    LeJemtel, T. H. (1992) A multicenter, randomized, double-blind,    placebo-controlled trial of pimobendan, a new cardiotonic and    vasodilator agent, in patients with severe congestive heart failure.    American Heart Journal 123: 95-103.-   Kubo, S. H., Gollub, S., Bourge, R., Rahko, P., Cobb, F., Jessup,    M., Brozena, S., Brodsky, M., Kirlin, P., and Shanes, J. (1992)    Beneficial effects of pimobendan on exercise tolerance and quality    of life in patients with heart failure. Results of a multicenter    trial. The Pimobendan Multicenter Research Group. Circulation 85:    942-949.-   Monnet, E., Orton, E. C., Salman, M., and Boon, J. (1995) Idiopathic    dilated cardiomyopathy in dogs: survival and prognostic indicators.    Journal of Veterinary Internal Medicine 9: 12-17.-   Packer, M., Carver, J. R., Rodeheffer, R. J., et al, and for the    PROMISE Study Research Group (1991) Effect of oral milrinone on    mortality in severe chronic heart failure. New England Journal of    Medicine 325: 1468-1475.

What is claimed is:
 1. A method for the treatment of a patient havingInternational Small Animal Cardiac Health Council (ISACHC) Class Iasymptomatic heart failure comprising: administering to a non-humanpatient having ISACHC Class I asymptomatic heart failure atherapeutically effective amount of a phosphodiesterase type III (PDEIII) inhibitor or a Ca²⁺-sensitizing agent selected from the groupconsisting of pimobendan, milrinone, levosimendan, amrinone, enoximone,and piroximone, wherein said therapeutically effective amount iseffective to prolong the time until onset of symptoms of ISACHC Class IIor Class III heart failure in the patient.
 2. The method according toclaim 1, wherein the asymptomatic heart failure is asymptomatic dilatedcardiomyopathy (DCM).
 3. The method according to claim 1, wherein thePDE III inhibitor additionally exhibits calcium sensitizing effects. 4.The method according to claim 1, wherein the PDE III inhibitor orCa²⁺-sensitizing agent is utilized in oral or parenteral form.
 5. Themethod according to claim 1, wherein the PDE III inhibitor orCa²⁺-sensitizing agent is administered in a daily dose from 10 μg/kg to10 mg/kg.
 6. The method according to claim 1, wherein said patient is amammal selected from the group consisting of non-human primates dogs,cats and horses.
 7. The method according to claim 1, wherein saidadministering step has the further effect of causing a reduction in thesize of the heart of the patient.
 8. A method for prolongation of thetime until onset of clinical symptoms in a patient having InternationalSmall Animal Cardiac Health Council (ISACHC) Class I asymptomatic heartfailure comprising: administering to a non-human patient having ISACHCClass I asymptomatic heart failure a therapeutically effective amount ofpimobendan.
 9. The method according to claim 8, wherein the asymptomaticheart failure is asymptomatic dilated cardiomyopathy (DCM).
 10. Themethod according to claim 8, wherein the pimobendan is utilized in oralor parenteral form.
 11. The method according to claim 8, wherein thepimobendan is administered in a daily dose from 10 μg/kg to 10 mg/kg.12. The method according to claim 8, wherein the patient is a mammalselected from the group consisting of non-human primates, dogs, cats andhorses.
 13. The method according to claim 8, wherein said administeringstep has the further effect of causing a reduction in the size of theheart of the patient.
 14. The method according to claim 8, wherein saidadministering step has the further effect of causing a prolongation ofthe time until the onset of symptoms in the patient.